LAUSR

Clinicians frequently must decide whether a patient's measurement reflects that of a healthy "normal" individual. Thus, the reference range is defined as the interval in which some proportion (frequently 95%) of measurements from a healthy population is expected to fall. One can estimate it from a single study or preferably from a meta-analysis of multiple studies to increase generalizability. This range differs from the confidence interval for the pooled mean or the prediction interval for a new study mean in a meta-analysis, which do not capture natural variation across healthy individuals. Methods for estimating the reference range from a meta-analysis of aggregate data that incorporate both within and between-study variations were recently proposed. In this guide, we present three approaches for estimating the reference range: a frequentist, a Bayesian, and an empirical method. Each method can be applied to either aggregate or individual participant data (IPD) meta-analysis, with the latter being the gold standard when available. We illustrate the application of these approaches to data from a previously published IPD meta-analysis evaluating the normal ranges of liver stiffness by transient elastography between 2006 and 2016.